MiR-221 Mediates Chemoresistance of Esophageal Adenocarcinoma by Direct Targeting of DKK2 Expression. Issue 5 (November 2016)

• Record Type: Journal Article
• Authors: Wang, Yan; Zhao, Yue; Herbst, Andreas; Kalinski, Thomas; Qin, Jiwei; Wang, Xiaoyan; Jiang, Zhenzhong; Benedix, Frank; Franke, Sabine; Wartman, Thomas; Camaj, Peter; Halangk, Walter; Kolligs, Frank T.; Jauch, Karl W.; Nelson, Peter J.; Bruns, Christiane J.
• Is Part Of: Annals of surgery. Volume 264:Issue 5(2016:Nov.)
• Publication Date: 2016-11
• Subjects: 5-FU resistance -- epithelial-mesenchymal transition -- esophageal cancer -- miR-221 -- Wnt/β-catenin signaling; Surgery -- Periodicals; 617.005
• DOI: 10.1097/SLA.0000000000001928
• Languages: English
• ISSNs: 0003-4932

Abstract

Abstract : Background: Chemoresistance is a main obstacle to effective esophageal cancer (EC) therapy. We hypothesize that altered expression of microRNAs (miRNAs) play a role in EC cancer progression and resistance to 5-fluorouracil (5-FU) based chemotherapeutic strategies. Methods: Four pairs of esophageal adenocarcinoma (EAC) cell lines and corresponding 5-FU resistant variants were established. The expression levels of miRNAs previously shown to be involved in the general regulation of stem cell pathways were analyzed by qRT-PCR. The effects of selected miRNAs on proliferation, apoptosis, and chemosensitivity were evaluated both in vitro and in vivo. We identified a particular miRNA and analyzed its putative target genes in 14 pairs of human EC tumor specimens with surrounding normal tissue by qRT-PCR as well as Wnt pathway associated genes by immunohistochemistry in another 45 EAC tumor samples. Results: MiR-221 was overexpressed in 5-FU resistant EC cell lines as well as in human EAC tissue. DKK 2 was identified as a target gene for miR-221. Knockdown of miR-221 in 5-FU resistant cells resulted in reduced cell proliferation, increased apoptosis, restored chemosensitivity, and led to inactivation of the Wnt/β-catenin pathway mediated by alteration in DKK2 expression. Moreover, miR-221 reduction resulted in alteration of EMT-associated genes such as E-cadherin and vimentin as well as significantly slower xenograft tumor growth in nude mice. RT 2 profiler analysis identified a substantial dysregulation of 4 Wnt/β-catenin signaling and chemoresistance target genes as a result of miR-221 modulation: CDH1, CD44, MYC, and ABCG2 . Conclusion: MiR-221 controls 5-FU resistance of EC partly via modulation of Wnt/β-catenin-EMT pathways by direct targeting of DKK2 expression. MiR-221 may serve as a prognostic marker and therapeutic target for patients with 5-FU resistant EAC. Abstract : Supplemental Digital Content is available in the text